IL300417A - Bifunctional benzothiophene compounds, preparations containing them and their use in therapy - Google Patents
Bifunctional benzothiophene compounds, preparations containing them and their use in therapyInfo
- Publication number
- IL300417A IL300417A IL300417A IL30041723A IL300417A IL 300417 A IL300417 A IL 300417A IL 300417 A IL300417 A IL 300417A IL 30041723 A IL30041723 A IL 30041723A IL 300417 A IL300417 A IL 300417A
- Authority
- IL
- Israel
- Prior art keywords
- optionally substituted
- group
- alkyl
- ulm
- substituted
- Prior art date
Links
- 230000001588 bifunctional effect Effects 0.000 title claims description 56
- 239000000203 mixture Substances 0.000 title claims description 42
- 238000011282 treatment Methods 0.000 title description 16
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title description 3
- -1 substituted Chemical class 0.000 claims description 318
- 150000001875 compounds Chemical class 0.000 claims description 220
- 125000003118 aryl group Chemical group 0.000 claims description 213
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 203
- 125000001072 heteroaryl group Chemical group 0.000 claims description 203
- 125000000217 alkyl group Chemical group 0.000 claims description 179
- 125000005647 linker group Chemical group 0.000 claims description 179
- 125000005843 halogen group Chemical group 0.000 claims description 153
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 133
- 229910052736 halogen Inorganic materials 0.000 claims description 115
- 125000000623 heterocyclic group Chemical group 0.000 claims description 115
- 150000002367 halogens Chemical class 0.000 claims description 101
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 98
- 229910052760 oxygen Inorganic materials 0.000 claims description 94
- 239000000126 substance Substances 0.000 claims description 91
- 229910052739 hydrogen Inorganic materials 0.000 claims description 87
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 82
- 229910052731 fluorine Inorganic materials 0.000 claims description 80
- 125000001424 substituent group Chemical group 0.000 claims description 80
- 229910052717 sulfur Inorganic materials 0.000 claims description 78
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 76
- 230000027455 binding Effects 0.000 claims description 72
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 70
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 claims description 67
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 claims description 67
- 229910052757 nitrogen Inorganic materials 0.000 claims description 67
- 229910052801 chlorine Inorganic materials 0.000 claims description 64
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 62
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 60
- 125000003107 substituted aryl group Chemical group 0.000 claims description 58
- 229910052799 carbon Inorganic materials 0.000 claims description 50
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 50
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 49
- 125000005842 heteroatom Chemical group 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 46
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 46
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 45
- 229910020008 S(O) Inorganic materials 0.000 claims description 42
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 42
- 125000004429 atom Chemical group 0.000 claims description 41
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 40
- 201000010099 disease Diseases 0.000 claims description 40
- 108010038795 estrogen receptors Proteins 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 39
- 125000003545 alkoxy group Chemical group 0.000 claims description 37
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 36
- 125000001188 haloalkyl group Chemical group 0.000 claims description 34
- 230000004481 post-translational protein modification Effects 0.000 claims description 32
- 150000003384 small molecules Chemical class 0.000 claims description 28
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 27
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- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 23
- 125000004122 cyclic group Chemical group 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 22
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 101000941994 Homo sapiens Protein cereblon Proteins 0.000 claims description 18
- 239000011737 fluorine Substances 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 17
- 150000001413 amino acids Chemical group 0.000 claims description 17
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 15
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 14
- 102000003960 Ligases Human genes 0.000 claims description 14
- 108090000364 Ligases Proteins 0.000 claims description 14
- 229940024606 amino acid Drugs 0.000 claims description 14
- 235000001014 amino acid Nutrition 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 230000008878 coupling Effects 0.000 claims description 12
- 238000010168 coupling process Methods 0.000 claims description 12
- 238000005859 coupling reaction Methods 0.000 claims description 12
- 235000019256 formaldehyde Nutrition 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
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- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
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- 208000035475 disorder Diseases 0.000 claims description 10
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
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- 239000003937 drug carrier Substances 0.000 claims description 9
- 239000012634 fragment Substances 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000002619 bicyclic group Chemical group 0.000 claims description 8
- 125000000524 functional group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 230000000707 stereoselective effect Effects 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- 239000000651 prodrug Substances 0.000 claims description 7
- 229960003433 thalidomide Drugs 0.000 claims description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical class C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 5
- 150000001204 N-oxides Chemical class 0.000 claims description 5
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 5
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 5
- 239000012867 bioactive agent Substances 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 5
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 claims description 5
- 229960000688 pomalidomide Drugs 0.000 claims description 5
- 208000024891 symptom Diseases 0.000 claims description 5
- OPYRETPBRCRXQU-UHFFFAOYSA-N 4,6-dihydro-1h-pyrrolo[3,2-b]pyrrol-5-one Chemical class N1C=CC2=C1CC(=O)N2 OPYRETPBRCRXQU-UHFFFAOYSA-N 0.000 claims description 4
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 4
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 4
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 4
- 102000015694 estrogen receptors Human genes 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 150000002462 imidazolines Chemical class 0.000 claims description 4
- 229960000310 isoleucine Drugs 0.000 claims description 4
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 claims description 4
- 150000003235 pyrrolidines Chemical class 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
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- 101001122499 Homo sapiens Nociceptin receptor Proteins 0.000 claims description 3
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- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
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- 239000004474 valine Substances 0.000 claims description 3
- HCMJWOGOISXSDL-UHFFFAOYSA-N (2-isothiocyanato-1-phenylethyl)benzene Chemical compound C=1C=CC=CC=1C(CN=C=S)C1=CC=CC=C1 HCMJWOGOISXSDL-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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